EP1128812B1 - 5-aminolävulinsäure-nanoemulsion - Google Patents

5-aminolävulinsäure-nanoemulsion Download PDF

Info

Publication number
EP1128812B1
EP1128812B1 EP99955981A EP99955981A EP1128812B1 EP 1128812 B1 EP1128812 B1 EP 1128812B1 EP 99955981 A EP99955981 A EP 99955981A EP 99955981 A EP99955981 A EP 99955981A EP 1128812 B1 EP1128812 B1 EP 1128812B1
Authority
EP
European Patent Office
Prior art keywords
composition
composition according
active substance
carrier
aminolevulinic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP99955981A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1128812A1 (de
Inventor
Hans W. Schmid
Gerd Burmeister
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
*BIOFRONTERA BIOSCIENCE G.M.B.H.HEMMELRATHER WEG 2
Original Assignee
ASAT AG Applied Science and Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ASAT AG Applied Science and Technology filed Critical ASAT AG Applied Science and Technology
Publication of EP1128812A1 publication Critical patent/EP1128812A1/de
Application granted granted Critical
Publication of EP1128812B1 publication Critical patent/EP1128812B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0061—5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to nanoemulsions containing 5-aminolevulinic acid, Derivatives, precursors or metabolites thereof.
  • Photodynamic therapy is a new and promising method for the treatment of various premalignant and malignant diseases, associated with cell proliferation.
  • the principle of Photodynamic therapy is based on a so-called photosensitizer into the tumor tissue and this by irradiation with light suitable wavelength in a cytotoxic active agent which ultimately causes the destruction of the cells.
  • the Selectivity of this method is due to a greater accumulation of the Sensitizer in rapidly proliferating tumor cells compared to Normal tissue.
  • a localized light irradiation can in the Tumor sensitizers are selectively activated, causing the Destroys cancer cells while largely protecting the healthy tissue become.
  • a reduction of high drug concentration in normal tissue and thus the unwanted side effects may, in certain cases, especially in dermatological and gynecological applications through the development of topically applicable drug formulations be achieved instead of the known systemic formulations.
  • to Reduction of photosensitivity is still trying to precursors use of photosensitizers which are photochemically inactive and first converted into a photosensitizer within the target cell become.
  • 5-aminolevulinic acid is an endogenous substance that consists of glycine and Succinyl-CoA is synthesized.
  • 5-aminolevulinic acid (5-ALA) in several fast-moving Reaction steps the highly photoactive protoporphyrin IX, the subsequently converted to haem in a slow reaction.
  • 5-ALA 5-aminolevulinic acid
  • One natural regulatory mechanism inhibits too high haem concentration both the body's own synthesis of 5-aminolevulinic acid and the Degradation of protoporphyrin IX.
  • protoporphyrin IX may be added Irradiation with light undergo a photochemical oxidation reaction and thus acts as a photosensitizer.
  • Sensibilisatormolekül By absorption of a light quantum by The Sensibilisatormolekül this is first in an electronic excited state (singlet state) offset, which is relatively short-lived and its excess energy either within a few nanoseconds by emitting a fluorescence photon again or in a relative long-lived triplet state passes. From this triplet state can Energy are transferred to existing in the cell oxygen molecules.
  • the resulting singlet oxygen is cytotoxic, in particular on proliferating cells since it can be treated with cell components, e.g. the cell membrane and mitochondria, or the formation of cell-damaging radicals triggers. Furthermore, the irradiation of the photosensitizer leads to a characteristic fluorescence radiation which is used for detection reactions, For example, be used to detect proliferating cells can.
  • Thiele et al. (H + G, volume 69, volume 3, pages 161-164 (1994)) describe investigations using 20% ⁇ -aminolevulinic acid in the form of an oil-in-water emulsion with a penetration time of 5 to 6 h and subsequent irradiation by means of an argon ion-pumped dye laser (emission maximum 630 nm) with a total cumulative dose of 50 to 100 J / cm 2 .
  • Hürlimann et al. disclose nanocolloid lotions containing 5-aminolevulinic acid as well their use in photodynamic therapy. Those nanocolloids however, have been used in the prior art using Egg lecithin produced as an emulsifier.
  • Another disadvantage of the known oil-in-water emulsions is that that the penetration depth of the photosensitizer into the damaged tissue is not optimal. As a result, in many cases, the diseased tissue is only in accessible to its superficial layers of photodynamic therapy, although the depth of penetration of the activation of the photosensitizer also used a treatment of deeper layers would allow.
  • the object of the present invention was therefore 5-aminolevulinic acid to provide containing compositions in which the from Prior art known disadvantages are at least partially eliminated and in particular have sufficient stability and a show improved penetration depth in tissue.
  • composition which thereby characterized in that it comprises a nanoemulsion comprising Active substance selected from 5-aminolevulinic acid, a salt, a Complex or an addition compound thereof, or / and to Protoporphyrin IX convertible precursors and / or a metabolite thereof and a carrier in an aqueous phase, whereof the carrier from one or more lipids and from one or more Emulsifiers comprising soy lecithin is formed.
  • Active substance selected from 5-aminolevulinic acid, a salt, a Complex or an addition compound thereof, or / and to Protoporphyrin IX convertible precursors and / or a metabolite thereof and a carrier in an aqueous phase, whereof the carrier from one or more lipids and from one or more Emulsifiers comprising soy lecithin is formed.
  • a third surprising advantage is that the invention in Nanosomes apparently packed very well with 5-aminolevulinic acid Cells is recorded. This will on the one hand an improved Targeting achieved, and on the other hand, the penetration time, i. of the Period between the application of the composition and the light irradiation be reduced to the diseased tissue, resulting in a patient represents noticeable relief.
  • the nanoemulsion comprises an active substance from 5-aminolevulinic acid, a derivative, a precursor or / and a Metabolites thereof.
  • derivative are in particular salts, complexes and To understand addition compounds.
  • precursor and metabolite are to be understood as meaning such subranges as in a cell Protoporphyrin IX be implemented.
  • the carrier can be any of one or more lipids and one or more several emulsifiers, including soya lecithin, be formed carrier, as long as he is capable of forming the nanoemulsion in an aqueous phase is.
  • the carrier comprises an oil phase, i. one not with Water-miscible material, e.g. Lipids, as well as an emulsifier. Appropriately, be physiologically harmless Carrier substances used.
  • the size of the emulsified particles in the nanoemulsion is on average ⁇ 200 nm, e.g. 10 to 200 nm.
  • the optimal one Particle size depends on other parameters, such as the Viscosity of the composition from. For example, were with a gel with a viscosity of 5 mPas at an average particle diameter from about 110 nm get good results and also for a lotion with a viscosity of 1.6 mPas at an average particle diameter of about 20 nm.
  • Suitable carrier systems which are stable over a long period, do not contain high concentrations of surfactants and cosurfactants and are free of toxic emulsifier complexes, e.g. in the US patent 5,152,923.
  • These nanoemulsions include as emulsifier Glycerophosphatide such as a lecithin or a cephalin and as Oil phase physiologically acceptable lipids, e.g. Triglycerides, such as vegetable or animal oils, e.g. Peanut oil, soy etc.
  • the Weight ratio of emulsifier / oil is from 0.05 to 0.4: 1.
  • Emulsifiers which are already in practice in 5-aminolevulinic acid nanoemulsions have been used successfully, for example Egg lecithin, soy lecithin and phosphatidylcholine.
  • a proven lipid is for example Miglyol 812.
  • the proportion of the active substance, e.g. 5-aminolevulinic acid in the Composition depends essentially on the intended Application from. In general, about 1 to 25 wt .-%, based on the total weight of the composition. higher however, lower dosages are feasible. For applications in the Related to photodynamic therapy, a proportion of 5 to 15 wt .-%, in particular of about 10 wt .-% proved suitable.
  • composition may further comprise auxiliaries and / or additives and in particular those substances which are used in cosmetics or Pharmacy are common.
  • auxiliaries and / or additives are for example buffers, Stabilizers, additional emulsifiers, thickeners, etc.
  • the inventive Composition a gel, which, based on the total weight of Composition 1 to 25% by weight, preferably 5 to 15% by weight Active substance, 40 to 60 wt .-%, preferably 45 to 55 wt .-% carrier, 0 to 10 wt .-%, preferably 1 to 5 wt .-% auxiliaries and the balance water includes.
  • the Composition according to the invention a lotion, which, based on the Total weight of the composition, 1 to 25 wt .-%, preferably 5 bis 15% by weight of active substance, 10 to 30% by weight, preferably 15 to 25% by weight Carrier, 10 to 30 wt .-%, preferably 15 to 25 wt .-% auxiliaries and the rest includes water.
  • the inventive 5-aminolevulinic acid composition a surprisingly high storage stability, the proportion active substance in a composition that has a pH between 1.5 and 3 after one year of storage at room temperature preferably not more than 5%, and more preferably not more is reduced by 4%. After one year of storage at 5 ° C, the proportion of Active substance preferably by not more than 3% and more preferably not reduced by more than 2.5%.
  • compositions according to the invention in the form of a pharmaceutical Preparation.
  • the composition is free of constituents, which are not pharmaceutically acceptable and are preferably free from Components which cause, for example, irritation.
  • the Pharmaceutical preparation can, in addition to those already mentioned Carrier substances contain other auxiliaries and / or additives, the acceptable and preferably well tolerated.
  • the pharmaceutical preparation may be in a form suitable for a systemic administration is suitable, such as an injectable Liquid.
  • the preparation is preferably in a form suitable for topical Application is suitable.
  • the preparation indicates the respectively desired Application form favorable properties, e.g. Viscosity and rheology, to ensure that after the application sufficient penetration the loaded with 5-aminolevulinic nanosomes in the target tissue he follows.
  • Viscosity and rheology properties can by Addition of thickeners, such as, for example, polyethylene glycol stearyl ethers, Polyethylene glycol stearates and / or polysaccharides such as about polysaccharide B-1459.
  • Another object of the present invention is a method for Production of the composition of the invention or the pharmaceutical preparation.
  • the 5-aminolevulinic acid and optionally present Additives can be added before or / and after homogenization become. After preparation of the nanoemulsion other auxiliary and Additives whose presence is not desired in the homogenization was to be admitted.
  • the process is preferably carried out under exclusion of air, for example by applying a vacuum and / or a Protective atmosphere. In addition, it is preferable to be in the absence of light work.
  • the process is carried out at a temperature at which the Training of the desired nanoemulsion can take place and a sufficient stability of the constituents, in particular the active substance given is. In general, a temperature range of about 5 to 45 ° C proved suitable.
  • auxiliary and / or Additives for example, initially in a separate approach and, if appropriate, homogenized, and only then can be added to the composition, but can also at higher Temperatures, for example, to about 80 ° C take place.
  • a sterility of the resulting Products e.g. by using sterile starting materials and Compliance with sterile process conditions and / or by a Sterilization step after production.
  • compositions are in the field of photodynamic therapy; wherein the nanoemulsion is particularly preferably applied topically.
  • the use of the nanoemulsion according to the invention is possible in all Diseases, the fight against proliferation inhibition or a Killing of cells or tissue by means of photoactivation of one of 5-aminolevulinic acid sensitizer formed.
  • a particularly high concentration of the Photosensitizer by the increased cell metabolism in diseased Cells takes place.
  • compositions according to the invention are therefore suitable for Treatment of tumor diseases, such as basal cell carcinomas, Squamous cell carcinoma, Bowen's disease, actinic keratosis, condylomata acuminata (CIN), epithelial neoplasia of the vulva (VIN), nodular and subcutaneous cancer.
  • tumor diseases such as basal cell carcinomas, Squamous cell carcinoma, Bowen's disease, actinic keratosis, condylomata acuminata (CIN), epithelial neoplasia of the vulva (VIN), nodular and subcutaneous cancer.
  • tumor diseases such as basal cell carcinomas, Squamous cell carcinoma, Bowen's disease, actinic keratosis, condylomata acuminata (CIN), epithelial neoplasia of the vulva (VIN), nodular and subcutaneous cancer.
  • CIN condylo
  • the treatment is carried out, for example, by topical application of a nanoemulsion containing the active substance, for example 5-aminolevulinic acid, and subsequent incubation in order to allow penetration of a sufficient amount of 5-aminolevulinic acid into the tissue to be treated.
  • a light irradiation on the treated site is preferably avoided, for example by covering, in order to prevent undesired premature activation.
  • the tissue is irradiated with a light source in a sufficient radiation dose.
  • Suitable light sources include lamps which emit white light and monochromatic light sources, such as a laser, in particular argon dye laser with an emission at about 630 nm.
  • the radiation doses are usually in a range from about 20 J / cm 2 to several 100 J / cm 2 per application.
  • Nanoemulsions relate to the detection of the presence of proliferating cells in a sample, e.g. a tissue sample.
  • a sample e.g. a tissue sample.
  • the Evidence is based on a selective enrichment of a Metabolization of the drug produced photosensitizer in the proliferating cells compared to normal cells.
  • the Active substance 5-aminolevulinic acid and the photosensitizer protoporphyrin IX are determined, e.g. by irradiating with Light with 405 nm wavelength and measuring by the photosensitizer generated fluorescence radiation.
  • the invention Nanoemulsions are especially for use in tumor diagnostics suitable.
  • Another object of the invention is the use of the nanoemulsion according to the invention for the manufacture of a medicament for the photodynamic therapy.
  • the invention relates to a kit which comprises an inventive, for topical application suitable nanoemulsion and one or more Contains aids.
  • aids are for example a Covering material, such as a plastic film, which after applying the Nanoemulsion is applied to the site to be treated to a prevent premature activation by light, means of attachment of the Covering material or means for applying the nanoemulsion on the body to be treated.
  • a nanocolloid carrier system according to the method of US Pat. No. 5,152,923 was prepared from egg lecithin (83% phosphatidylcholine), miglyol 812 (triglyceride) and polysorbate 80 in a phosphate buffer.
  • the analysis data of the carrier system were as shown in Table 1.
  • Viscosity (20 ° C) 1.6 mPas Size of the nanoparticles ⁇ 10-200 nm average diameter 19.4 nm
  • Egg lecithin content 17.5 mg / ml
  • Polysorbate 80 content ⁇ 3% (w / w)
  • Miglyol 812 content 34-38 mg / ml Aerobic mesophilic germs in 50 ml ⁇ 1 CFU / ml
  • Phase 1 was prepared by Melting of the components according to Table 2 in the given proportions at 80 ° C and then mixing.
  • Phase 2 was prepared in a separate vessel. This was the Submitted water and the remaining components according to Table 2 below Stirring added. After sufficient mixing, Phase 2 became 80 ° C heated and mixed under vacuum to phase 1.
  • Phase 3 was in a separate vessel under vacuum and light exclusion produced.
  • the nanocolloid carrier system was as above described and the 5-Aminolävulinklahydrochlorid at 25 to 30 ° C dissolved in it.
  • phase 3 was at 40 ° C under vacuum added to the mixture of phases 1 and 2.
  • the composition was then gassed with inert gas and in a homogenizer for 2 to 3 minutes homogenized. It was then stirred to room temperature allowed to cool.
  • the 5-ALA content was after One-year storage at 5 ° C 97.92% of the original content, at Room temperature was given a value of 96.50% in the same period.
  • a nanocolloid carrier system was prepared according to the method of US Pat. No. 5,152,923 from egg lecithin and Miglyol 812 (triglyceride) in a K / Na phosphate buffer.
  • the analysis data was as shown in Table 3.
  • phase 1 For the preparation of phase 1, the water was initially charged, at 60 to 70 ° C. heated and then Keltrol dispersed in a vacuum. The Mixture was homogenized for 4 min at stage 1, then stirred up Allow step 1 to cool to 30 ° C.
  • the nanocarrier system was in a placed under vacuum at room temperature, and the 5-aminolevulinic acid hydrochloride was stirred for 2 to 3 hours completely solved.
  • phase 2 was mixed under vacuum to phase 1 and then fumigated with nitrogen.
  • the resulting composition was at a temperature of not more than 30 ° C for 2 hours with stirring homogeneous mixed.
  • the effect of the nanolotion according to the invention was in a clinical Study of 55 basal cell carcinomas in a 19-patient population People examined.
  • the entire skin area to be treated was cleaned with an alcoholic solution.
  • Each 0.15 g of nanocolloid solution per cm 2 of skin area to be treated was applied, resulting in a thin, visible lotion film.
  • the entire surface was covered with an opaque cover material to prevent smearing of the lotion and ambient light induced undesirable photodynamic reactions.
  • the cover was removed and the presence of protoporphyrin IX and the extent of the tumor were assessed by the characteristic red fluorescence of porphyrins upon irradiation with ultraviolet light.
  • the irradiation was carried out with unfiltered light from a 250 W halogen lamp with a spectral distribution over the entire visible range at a maximum of about 800 nm. All lesions were irradiated at a distance of 10 cm, which irradiated areas with a diameter up to 10 cm allowed.
  • the irradiation time was 20 min at an intensity of 200 mW / cm 2 , corresponding to a total light dose of 240 J / cm 2 .
  • the number of treated tumors in different body areas were 11 (20%) in the head and Neck area, 37 (67%) in the trunk area, 3 (5%) on the upper Limbs and 4 (7%) on the lower limbs.
  • Treatment was routinely taken from biopsies to help diagnose to confirm. Therapy success was assessed by visual inspection and Palpation and in 26 (47%) of the tumors also by histopathological Investigations. In the absence of a clinically detectable tumor at the treatment site at the follow-up was called Full tumor response defined. A noticeable reduction in tumor size was defined as tumor part response.
  • Table 6 shows the results of photodynamic therapy as a function of the localization of basal cell carcinomas. The best results were obtained for the seven lesions on the limbs, which decreased completely. Out of 37 rump lesions, 32 tumors completely receded and of 11 tumors in the head and neck area, 8 (76%) completely decreased. visual assessment biopsy Number of patients 19 13 Basal cell carcinomas 55 26 Completely. decline 47 (85%) 21 (81%) part decline 8 (15%) 5 (19%) no reaction - - Head and neck hull limbs Number of patients 6 12 4 Basal cell carcinomas 11 37 7 completely empty. decline 8 (73%) 32 (86%) 7 (100%) part decline 3 (27%) 5 (14%) - no reaction - - -
  • the effect of the nanoemulsion according to the invention in the form of a gel was in a clinical study of photodynamic therapy of Kondylomata acuminata and intraepithelial neoplasia of the vulva (VIN) 47 lesions a group of 16 patients with an age of 18 to 45 years (average age 32.7 years) studied.
  • the gel was applied as described in Example 3 for the lotion, except that the incubation time for the diffusion of 5-aminolevulinic acid was only 90 minutes. Irradiation was carried out using an argon dye laser (Coherent Innova, Model 310, Palo Alto, CA) with monochromatic light (630 nm) and with light doses between 50 J / cm 2 and 125 J / cm 2 .
  • an argon dye laser Coherent Innova, Model 310, Palo Alto, CA
  • monochromatic light 630 nm
  • light doses between 50 J / cm 2 and 125 J / cm 2 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Radiation-Therapy Devices (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
EP99955981A 1998-11-12 1999-11-12 5-aminolävulinsäure-nanoemulsion Expired - Lifetime EP1128812B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19852245 1998-11-12
DE19852245A DE19852245A1 (de) 1998-11-12 1998-11-12 5-Aminolävulinsäure-Nanoemulsion
PCT/EP1999/008711 WO2000028971A1 (de) 1998-11-12 1999-11-12 5-aminolävulinsäure-nanoemulsion

Publications (2)

Publication Number Publication Date
EP1128812A1 EP1128812A1 (de) 2001-09-05
EP1128812B1 true EP1128812B1 (de) 2004-02-25

Family

ID=7887602

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99955981A Expired - Lifetime EP1128812B1 (de) 1998-11-12 1999-11-12 5-aminolävulinsäure-nanoemulsion

Country Status (13)

Country Link
US (1) US6559183B1 (xx)
EP (1) EP1128812B1 (xx)
JP (1) JP2002529495A (xx)
AT (1) ATE260092T1 (xx)
AU (1) AU758098B2 (xx)
CA (1) CA2351620C (xx)
DE (2) DE19852245A1 (xx)
HK (1) HK1039893A1 (xx)
IL (2) IL142876A0 (xx)
NZ (1) NZ511351A (xx)
PT (1) PT1128812E (xx)
WO (1) WO2000028971A1 (xx)
ZA (1) ZA200104726B (xx)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3970492B2 (ja) * 1999-12-14 2007-09-05 コスモ石油株式会社 ピーリング用組成物
DE10034673C1 (de) * 2000-07-17 2002-04-25 Medac Klinische Spezialpraep Dermales Applikationssystem für Aminolävulinsäure und seine Verwendung
DE10063076A1 (de) * 2000-12-18 2002-06-27 Medac Klinische Spezialpraep Verwendung von 5-Aminolävulinsäure zur Restenose-Prophylaxe
DE10202487A1 (de) 2002-01-23 2003-07-31 Photonamic Gmbh & Co Kg Dermales Applikationssystem für Aminolävulinsäure-Derivate
US20040048842A1 (en) * 2002-09-10 2004-03-11 Mcmillan Kathleen Method of treating skin disorders
DE10301917B4 (de) * 2003-01-17 2007-02-01 Gerhard Saalmann Verwendung von Substanzen der Porphyrinsynthese bei der Phototherapie von Haut- oder Gelenkerkrankungen des Menschen oder von Säugetieren
ATE493382T1 (de) * 2004-03-30 2011-01-15 Cosmo Oil Co Ltd 5-aminolevulinsäure-phosphatsalz, verfahren zu dessen herstellung und dessen verwendung
WO2006098966A2 (en) * 2005-03-09 2006-09-21 Combe Incorporated Stable mixed emulsions comprising semisolid dispersions of at least two discrete and distinctly different particle size ranges
US20060222592A1 (en) * 2005-04-05 2006-10-05 Clemens Burda Nanoparticles and methods of manufacturing nanoparticles for electronic and non-electronic applications
CA2600288A1 (en) * 2005-09-19 2007-04-12 Combe Incorporated Stable emulsion systems with high salt tolerance
EP1938801A1 (en) * 2006-12-22 2008-07-02 Biofrontera Bioscience GmbH Nanoemulsion
WO2008102065A1 (fr) * 2007-02-14 2008-08-28 Commissariat A L'energie Atomique Emulsions fluorescentes pour l'imagerie optique
FR2934953B1 (fr) 2008-08-14 2011-01-21 Commissariat Energie Atomique Nanoemulsions de nanocristaux
FR2935001B1 (fr) * 2008-08-14 2011-12-30 Commissariat Energie Atomique Emulsion fluorescente
FR2934954B1 (fr) 2008-08-14 2011-07-22 Commissariat Energie Atomique Emulsion fluorescente de vert d'indocyanine
FR2934955B1 (fr) * 2008-08-14 2011-07-08 Commissariat Energie Atomique Encapsulation d'agents therapeutiques lipophiles ou amphiphiles dans des nanoemulsions
CN103270168A (zh) 2010-12-24 2013-08-28 爱科来株式会社 癌细胞的检测方法
US9241921B2 (en) 2011-05-02 2016-01-26 Pankaj Modi Photosensitizer composition for treating skin disorders
US10603508B2 (en) 2015-10-15 2020-03-31 Dusa Pharmaceuticals, Inc. Adjustable illuminators and methods for photodynamic therapy and diagnosis
EP3851161A1 (en) 2015-10-15 2021-07-21 DUSA Pharmaceuticals, Inc. Adjustable illuminator for photodynamic therapy and diagnosis
CN105708788B (zh) * 2016-02-24 2018-12-21 济南梵康医疗科技有限公司 一种盐酸氨基酮戊酸纳米乳膏的制备方法
WO2018221291A1 (ja) * 2017-05-31 2018-12-06 Ｓｂｉファーマ株式会社 過活動膀胱の予防剤または治療剤
AU2018302103B2 (en) * 2017-07-17 2024-03-07 Sun Pharmaceutical Industries, Inc. Photodynamic therapy method for skin disorders
CN107233303A (zh) * 2017-08-07 2017-10-10 苏州纳美特生物科技有限公司 一种氨基酮戊酸冷霜及其制备方法和应用
US10357567B1 (en) 2018-01-12 2019-07-23 Dusa Pharmaceuticals, Inc. Methods for photodynamic therapy
US11198831B2 (en) 2019-01-31 2021-12-14 Kvi Llc Lubricant for a device

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963367A (en) 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
CN1039283C (zh) * 1988-12-12 1998-07-29 Fmc公司 卟啉的应用
CH677886A5 (xx) 1989-06-26 1991-07-15 Hans Georg Prof Dr Weder
CA2087902C (en) * 1992-02-05 2006-10-17 Narendra Raghunathji Desai Liposome compositions of porphyrin photosensitizers
US5599831A (en) * 1994-05-27 1997-02-04 Poretz; Ronald D. Method of preparation of pharmaceutical compositions
EP0704209A1 (en) * 1994-09-20 1996-04-03 JOHNSON & JOHNSON MEDICAL, INC. Transdermally active pharmaceutical composition containing 5-aminolaevulinic acid
FR2730932B1 (fr) * 1995-02-27 1997-04-04 Oreal Nanoemulsion transparente a base de lipides amphiphiles non-ioniques fluides et utilisation en cosmetique ou en dermopharmacie
HU225148B1 (en) * 1995-03-10 2006-07-28 Photocure Asa Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy or diagnosis, products and kits comprising thereof and method of in vitro diagnosis by their using
US5616342A (en) * 1995-04-11 1997-04-01 Pdt, Inc. Emulsioin suitable for administering a poorly water-soluble photosensitizing compound and use thereof

Also Published As

Publication number Publication date
CA2351620C (en) 2006-01-10
IL142876A (en) 2007-06-03
AU1271000A (en) 2000-06-05
DE59908665D1 (de) 2004-04-01
AU758098B2 (en) 2003-03-13
ATE260092T1 (de) 2004-03-15
WO2000028971A1 (de) 2000-05-25
CA2351620A1 (en) 2000-05-25
HK1039893A1 (zh) 2002-05-17
PT1128812E (pt) 2004-09-30
DE19852245A1 (de) 2000-05-18
NZ511351A (en) 2003-08-29
ZA200104726B (en) 2002-01-21
IL142876A0 (en) 2002-03-10
US6559183B1 (en) 2003-05-06
JP2002529495A (ja) 2002-09-10
EP1128812A1 (de) 2001-09-05

Similar Documents

Publication Publication Date Title
EP1128812B1 (de) 5-aminolävulinsäure-nanoemulsion
DE69027057T2 (de) Retinal, dessen Derivate und deren therapeutische Verwendung
DE3874428T2 (de) Maulbeerbaumextrakte enthaltende liposomzusammensetzung.
DE69029804T2 (de) VEHIKEL MIT LANGSAMER FREISETZUNG ZUR VERMINDERUNG DER HAUTREIZUNG TOPISCHER retinoidhaltiger MITTEL
DE69632858T2 (de) Zur verabreichnung einer schlecht wasserlöslichen photosensibilisierenden verbindung geeignete emulsion und deren verwendung
DE68910520T2 (de) Verfahren zur Verminderung von Hautirritationen bei Anwendung von durchdringungsverstärkenden Arzneimittelzusammensetzungen.
DE602004004399T2 (de) Grün gefärbte topische pharmazeutische zusammensetzung auf der basis von metronidazol
DE69725843T2 (de) Mittel zur verwendung in der phototherapeutischen behandlung proliferativer hautstörungen
EP1255725B1 (de) 5-aminolävulinsäure-formulierung in nichtwässrigen lösungsmitteln
DE3119017A1 (de) Entzuendungshemmende und analgetische gel-zusammensetzungen
JP2011506425A (ja) 治療的及び美容的方法に有用な新規化合物
EP1716845B1 (de) Formulierung zur dermalen Anwendung
DE69302396T2 (de) Antiviral wirksame pharmazeutische öl in wasser-emulsion, die 9-[(2-hydroxyethoxy)methyl]-guanin (acyclovir) oder ein salz oder einen ester davon enthält
DE69305433T2 (de) Kosmetische oder dermatologische Zusammensetzung zur Hautdepigmentierung enthaltend eine di- oder tri-Kaffeoylchinasäure oder eine Mischung davon
DE2841346A1 (de) Mittel zur behandlung der haut mit antiviraler wirkung
DE69202272T2 (de) Hautfärbende Zusammensetzung, die Indolderivate und Dihydroxyazeton enthält.
DE69600871T3 (de) Filtrierende Zusammensetzung für die kosmetische oder dermatologische Verwendung, die einen Chelat-Bildner für Eisen enthält
DE2748399A1 (de) Antimikrobielles mittel zur oertlichen anwendung
DE2707814A1 (de) Mittel zur pflege und behandlung der haut und verfahren zur herstellung der mittel
DE68903736T2 (de) Stabilisierte 2-phenyl-1,2-benzisoselenazol-3(2h)-on enthaltende, parenteral anzuwendende loesung und verfahren zu deren herstellung.
KR920006906B1 (ko) 히드로퀴논 및 코지산을 함유하는 제약 또는 화장제 조성물
DE19744811C2 (de) Verwendung von delta-Aminolävulinsäure zur Herstellung eines topischen Arzneimittels zur integralen Diagnose und/oder Therapie von Tumoren in Hohlorganen
DE60120159T2 (de) Hautpflegemittel
DE69000960T2 (de) Zusammensetzung zur behandlung von pigmentierung.
DE2338833A1 (de) Fuer pharmazeutische und/oder kosmetische zwecke brauchbares lichtschutzpraeparat

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010508

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20030327

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040225

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20040225

Ref country code: GB

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040225

Ref country code: FR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040225

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040225

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040225

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: GERMAN

REF Corresponds to:

Ref document number: 59908665

Country of ref document: DE

Date of ref document: 20040401

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040525

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040525

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040525

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040605

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: A. BRAUN, BRAUN, HERITIER, ESCHMANN AG PATENTANWAE

GBV Gb: ep patent (uk) treated as always having been void in accordance with gb section 77(7)/1977 [no translation filed]

Effective date: 20040225

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20040722

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20041130

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

REG Reference to a national code

Ref country code: PT

Ref legal event code: TE4A

Owner name: ASAT AG APPLIED SCIENCE & TECHNOLOGY, CH

Effective date: 20041125

EN Fr: translation not filed
26N No opposition filed

Effective date: 20041126

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: BIOFRONTERA PHARMACEUTICALS GMBH

Free format text: ASAT AG APPLIED SCIENCE & TECHNOLOGY#BAARERSTRASSE 77#6302 ZUG (CH) -TRANSFER TO- BIOFRONTERA PHARMACEUTICALS GMBH#HEMMELRATHER WEG 201#51377 LEVERKUSEN (DE)

Ref country code: CH

Ref legal event code: PFA

Owner name: BIOFRONTERA BIOSCIENCE GMBH

Free format text: BIOFRONTERA PHARMACEUTICALS GMBH#HEMMELRATHER WEG 201#51377 LEVERKUSEN (DE) -TRANSFER TO- BIOFRONTERA BIOSCIENCE GMBH#HEMMELRATHER WEG 201#51377 LEVERKUSEN (DE)

BECA Be: change of holder's address

Owner name: *BIOFRONTERA BIOSCIENCE G.M.B.H.HEMMELRATHER WEG 2

Effective date: 20060118

BECN Be: change of holder's name

Owner name: *BIOFRONTERA BIOSCIENCE G.M.B.H.HEMMELRATHER WEG 2

Effective date: 20060118

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1039893

Country of ref document: HK

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: BIOFRONTERA BIOSCIENCE GMBH

Free format text: BIOFRONTERA BIOSCIENCE GMBH#HEMMELRATHER WEG 201#51377 LEVERKUSEN (DE) -TRANSFER TO- BIOFRONTERA BIOSCIENCE GMBH#HEMMELRATHER WEG 201#51377 LEVERKUSEN (DE)

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: NEW ADDRESS: HOLBEINSTRASSE 36-38, 4051 BASEL (CH)

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20151119

Year of fee payment: 17

Ref country code: LU

Payment date: 20151119

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20151118

Year of fee payment: 17

Ref country code: PT

Payment date: 20151110

Year of fee payment: 17

Ref country code: AT

Payment date: 20151119

Year of fee payment: 17

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161130

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 260092

Country of ref document: AT

Kind code of ref document: T

Effective date: 20161112

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170515

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161112

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161112

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20161130

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20180814

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20181120

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 59908665

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL